US4129731A - Process for converting 3-methylene cephalosporins to 3-heterothiomethyl cephalosporins - Google Patents
Process for converting 3-methylene cephalosporins to 3-heterothiomethyl cephalosporins Download PDFInfo
- Publication number
- US4129731A US4129731A US05/748,426 US74842676A US4129731A US 4129731 A US4129731 A US 4129731A US 74842676 A US74842676 A US 74842676A US 4129731 A US4129731 A US 4129731A
- Authority
- US
- United States
- Prior art keywords
- hydrogen
- formula
- methyl
- group
- hetero
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- 3-Methylene cephalosporanic acid esters are described as a by product in the conversion of penicillin sulfoxides to cephalosporins by Morin et al. in U.S. Pat. No. 3,275,626.
- Ponticello et al. in U.S. Pat. No. 3,883,518 describe the preparation of various acylated 3-methylene cephalosporins including those having a 7 ⁇ -methoxy substituent. Ponticello et al. describe reacting the methylene compound with a source of halogen to yield an acylated 3-halo-3-halomethyl cephalosporin which is treated with base to yield the acylated 3-halomethyl compound.
- This invention relates to the preparation of 3-heterothiomethyl cephalosporanic acid esters of the formula ##STR3## in a one step process by treating a 3-methylene compound of the formula ##STR4## with a compound of the formula
- the lower alkyl groups referred to throughout this specification include straight or branched chain hydrocarbon groups containing 1 to 4 carbon atoms. Examples of the type of groups contemplated are methyl, ethyl, n-propyl, isopropyl, t-butyl, etc.
- the lower alkoxy groups include such lower groups attached to an oxygen, e.g., methoxy, ethoxy, propoxy, etc.
- R represents a readily removable ester group such as t-butyl, diphenylmethyl, trimethylsilyl, t-butyl dimethylsilyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, or 2,2,2-trichloroethyl.
- R 1 is in the ⁇ -configuration and is hydrogen or methoxy.
- hetero represents the following groups ##STR5## wherein R 2 is hydrogen or lower alkyl 1 to 4 carbons (preferably methyl or ethyl).
- acyl represents those sidechains known in the cephalosporin art which can withstand the reaction with the compound of formula III or IV and which have been coupled with or are readily modified to provide sidechains that have been coupled with the cephalosporin nucleus to provide antibacterially active compounds, or which can be readily cleaved to yield the corresponding 7 ⁇ -amino-7 ⁇ -methoxy or desmethoxy-3-heterothiomethyl cephalosporanic acid ester.
- acyl groups include lower ##STR6## wherein R 3 is hydrogen, Cl, Br, lower alkyl (preferably methyl or ethyl), or lower alkoxy (preferably methoxy or ethoxy), R 4 is hydrogen, Cl, Br, or lower alkyl (preferably methyl or ethyl), and R 5 is hydrogen or protected amino of the formula ##STR7## or protected hydroxy of the formula -O-R 7 wherein R 6 is t-butyl-oxycarbonyl, benzylcarbonyl, substituted benzyloxycarbonyl wherein the substituent is on the phenyl ring and is methyl, methoxy, nitro, Br or Cl, trichloroethyloxycarbonyl, adamantyloxycarbonyl, trifluoroacetyl, chloroacetyl, succinyl, phthaloyl, or formyl, preferably t-butyloxycarbonyl, substituted or unsubstituted benz
- X represents halogen, i.e. Br, Cl, F, or I, preferably Br or Cl, lower alkoxycarbonylthio, preferably methoxycarbonylthio, phthalimido, succinimido, or a sulfonyl of the formula ##STR8## wherein Z is lower alkyl, phenyl, or phenyl having a methyl, methoxy, nitro, Br, or Cl substituent.
- the reaction between the 3-methylene compound of formula II and the thiolating compound of formula III or IV is performed in an inert organic solvent and in the presence of one or two equivalents of an alkali metal base or an organic base at a temperature of from about -80° C to about 20° C for from about 5 minutes to about 3 hours.
- the reaction is performed under an inert atmosphere such as nitrogen or argon.
- Suitable inert organic solvents for this reaction include tetrahydrofuran, ethyl ether, dioxane, acetonitrile, dimethoxyethane, dimethylformamide, dimethylsulfoxide, and dimethylacetamide.
- Suitable alkali metal bases include potassium t-butoxide, lithium diethylamide, lithium diisopropylamide, lithium N-cyclohexylisopropylamide, and lithium hexamethyldisilzane.
- Suitable organic bases include 1,5-diazobicyclo-[5.4.0]undec-5-ene and 1,5-diazabicyclo[4.3.0]non-5-ene.
- the 3-heterothiomethyl cephalosporanic acid ester of formula I prepared according to this invention can be treated in several ways to yield a valuable antibacterially active compound.
- the acyl sidechain of the compound of formula I is the desired acyl sidechain of the antibacterially active compound, i.e. where acyl is phenylacetyl, (2-thienyl)acetyl, etc.
- the only additional process involves removal of the carboxylic acid ester protecting group by acidic or basic hydrolysis as known in the art.
- the additional process steps would involve removal of this protecting group as well as removal of the carboxylic acid ester protecting group according to methods known in the art as note, for example, U.S. Pat. Nos. 3,641,021, 3,796,801, 3,932,393, 3,855,213, etc.
- the resulting ⁇ -amino compound can be reacted with an alkali metal cyanate or alkaline earth metal cyanate as taught in U.S. Pat. Nos. 3,978,051 and 3,989,697 to yield the corresponding ⁇ -ureido compound or reacted according to the procedure of U.S. Pat. No. 3,925,368 or 3,956,292 to yield various ⁇ -acylated ureido compounds.
- the residue is purified by chromatography on three 20 ⁇ 20 ⁇ cm. ⁇ 1 mm. silica gel plates in the system acetone-acetic acid (16:1). Elution of the band R f ⁇ 0.6 with acetone-methanol (3:1) followed by removal of the solvent yields a residue.
- the residue is taken up in ethyl acetate-water, the pH is adjusted to 7.5 by the addition of aqueous sodium bicarbonate, and after extracting, the aqueous layer is covered with fresh ethyl acetate and the pH adjusted to 2 by the addition of 1N HCl.
- the mixture is stirred at -70° for 30 minutes and then poured into a pH 6.6 phosphate buffer and ethyl acetate. After repeated extraction with ethyl acetate, the combined ethyl acetate extract is washed successively with dilute HCl, water, and saturated NaCl solution. After drying (MgSO 4 ), the ethyl acetate extract is evaporated in vacuo to yield 342 mg. of crude product.
- the isolated product of Col. IV will be in the form of the free acid (i.e. R is hydrogen) as in example 1 since the silyl ester is hydrolyzed off during the extraction steps.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/748,426 US4129731A (en) | 1976-12-08 | 1976-12-08 | Process for converting 3-methylene cephalosporins to 3-heterothiomethyl cephalosporins |
CA289,795A CA1087169A (en) | 1976-12-08 | 1977-10-28 | Process for converting 3-methylene cephalosporins to 3-heterothiomethyl cephalosporins |
AU30386/77A AU511186B2 (en) | 1976-12-08 | 1977-11-07 | Conversioni of 3-methylene celphalosporins to 3-hetero-thiomethyl celphalosprins |
GB48627/77A GB1591460A (en) | 1976-12-08 | 1977-11-22 | Preparation of 3-heterocyclylthiomethyl cephalosporins from 3-methylene cephalosporins |
NL7712900A NL7712900A (nl) | 1976-12-08 | 1977-11-23 | Werkwijze voor de bereiding van nieuwe 3-heterothiomethylcefalosporaanzure esters. |
IE2411/77A IE46175B1 (en) | 1976-12-08 | 1977-11-28 | Preparation of 3-heterocyclylthiomethyl cephalosporins from 3-methylene cephalosporins |
FR7736436A FR2373549A1 (fr) | 1976-12-08 | 1977-12-02 | Procede de transformation de 3-methylenecephalosporines en 3-heterothiomethylcephalosporines |
CH1502277A CH626089A5 (sl) | 1976-12-08 | 1977-12-07 | |
JP14915677A JPS5373597A (en) | 1976-12-08 | 1977-12-08 | Process for preparing 33heterothiomethylcepualospolines |
BE183281A BE861639A (fr) | 1976-12-08 | 1977-12-08 | Procede de conversion de 3-methylene cephalosporines en 3-heterothiomethyl cephalosporines |
DE2754742A DE2754742C2 (de) | 1976-12-08 | 1977-12-08 | Verfahren zur Herstellung von substituierten Cephalosporansäureestern |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/748,426 US4129731A (en) | 1976-12-08 | 1976-12-08 | Process for converting 3-methylene cephalosporins to 3-heterothiomethyl cephalosporins |
Publications (1)
Publication Number | Publication Date |
---|---|
US4129731A true US4129731A (en) | 1978-12-12 |
Family
ID=25009398
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US05/748,426 Expired - Lifetime US4129731A (en) | 1976-12-08 | 1976-12-08 | Process for converting 3-methylene cephalosporins to 3-heterothiomethyl cephalosporins |
Country Status (11)
Country | Link |
---|---|
US (1) | US4129731A (sl) |
JP (1) | JPS5373597A (sl) |
AU (1) | AU511186B2 (sl) |
BE (1) | BE861639A (sl) |
CA (1) | CA1087169A (sl) |
CH (1) | CH626089A5 (sl) |
DE (1) | DE2754742C2 (sl) |
FR (1) | FR2373549A1 (sl) |
GB (1) | GB1591460A (sl) |
IE (1) | IE46175B1 (sl) |
NL (1) | NL7712900A (sl) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4311837A (en) * | 1979-05-01 | 1982-01-19 | Eli Lilly And Company | Certain heterocyclic thiomethyl derivatives of 7-(dihalogenated phenylthioacetamido)cephalosporanic acids useful in the treatment of infections caused by _Streptococcus faecalis |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL8005041A (nl) * | 1980-09-05 | 1982-04-01 | Gist Brocades Nv | Werkwijze voor de bereiding van thioethers, alsmede gesilyleerde thiolen voor toepassing bij deze werkwijze. |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3275626A (en) * | 1962-07-31 | 1966-09-27 | Lilly Co Eli | Penicillin conversion via sulfoxide |
US3792995A (en) * | 1971-04-05 | 1974-02-19 | Takeda Chemical Industries Ltd | Process for producing cephalosporin derivatives |
US3883518A (en) * | 1972-05-15 | 1975-05-13 | Merck & Co Inc | 3-Methylene cephalosporins |
US3925372A (en) * | 1973-02-23 | 1975-12-09 | Lilly Co Eli | Alpha-aminoacyl-3-halo cephalosporins |
US3929775A (en) * | 1970-12-08 | 1975-12-30 | Takeda Chemical Industries Ltd | Process for producing cephalosporin derivatives |
US3932393A (en) * | 1971-02-25 | 1976-01-13 | Eli Lilly And Company | 3-Methylenecephalosporins and process for production thereof |
US3941779A (en) * | 1973-11-12 | 1976-03-02 | E. R. Squibb & Sons, Inc. | Method for producing 2-(substituted thio)-3-cephem derivatives |
US3962227A (en) * | 1973-02-23 | 1976-06-08 | Eli Lilly And Company | 3-halo cephalosporins |
US3968109A (en) * | 1973-11-23 | 1976-07-06 | E. R. Squibb & Sons, Inc. | Production of 2-(thio substituted)cephalosporin sulfoxides and 2-(thio substituted)cephalosporins |
US4039534A (en) * | 1975-11-17 | 1977-08-02 | E. R. Squibb & Sons, Inc. | 4-Thio substituted-Δ2 -cephalosporin intermediates |
US4049806A (en) * | 1975-08-15 | 1977-09-20 | Syntex (U.S.A.) Inc. | Cephalosporin type antibacterials |
-
1976
- 1976-12-08 US US05/748,426 patent/US4129731A/en not_active Expired - Lifetime
-
1977
- 1977-10-28 CA CA289,795A patent/CA1087169A/en not_active Expired
- 1977-11-07 AU AU30386/77A patent/AU511186B2/en not_active Expired
- 1977-11-22 GB GB48627/77A patent/GB1591460A/en not_active Expired
- 1977-11-23 NL NL7712900A patent/NL7712900A/xx not_active Application Discontinuation
- 1977-11-28 IE IE2411/77A patent/IE46175B1/en not_active IP Right Cessation
- 1977-12-02 FR FR7736436A patent/FR2373549A1/fr active Granted
- 1977-12-07 CH CH1502277A patent/CH626089A5/fr not_active IP Right Cessation
- 1977-12-08 BE BE183281A patent/BE861639A/xx not_active IP Right Cessation
- 1977-12-08 DE DE2754742A patent/DE2754742C2/de not_active Expired
- 1977-12-08 JP JP14915677A patent/JPS5373597A/ja active Granted
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3275626A (en) * | 1962-07-31 | 1966-09-27 | Lilly Co Eli | Penicillin conversion via sulfoxide |
US3929775A (en) * | 1970-12-08 | 1975-12-30 | Takeda Chemical Industries Ltd | Process for producing cephalosporin derivatives |
US3932393A (en) * | 1971-02-25 | 1976-01-13 | Eli Lilly And Company | 3-Methylenecephalosporins and process for production thereof |
US3792995A (en) * | 1971-04-05 | 1974-02-19 | Takeda Chemical Industries Ltd | Process for producing cephalosporin derivatives |
US3883518A (en) * | 1972-05-15 | 1975-05-13 | Merck & Co Inc | 3-Methylene cephalosporins |
US3925372A (en) * | 1973-02-23 | 1975-12-09 | Lilly Co Eli | Alpha-aminoacyl-3-halo cephalosporins |
US3962227A (en) * | 1973-02-23 | 1976-06-08 | Eli Lilly And Company | 3-halo cephalosporins |
US3941779A (en) * | 1973-11-12 | 1976-03-02 | E. R. Squibb & Sons, Inc. | Method for producing 2-(substituted thio)-3-cephem derivatives |
US3968109A (en) * | 1973-11-23 | 1976-07-06 | E. R. Squibb & Sons, Inc. | Production of 2-(thio substituted)cephalosporin sulfoxides and 2-(thio substituted)cephalosporins |
US4049806A (en) * | 1975-08-15 | 1977-09-20 | Syntex (U.S.A.) Inc. | Cephalosporin type antibacterials |
US4039534A (en) * | 1975-11-17 | 1977-08-02 | E. R. Squibb & Sons, Inc. | 4-Thio substituted-Δ2 -cephalosporin intermediates |
Non-Patent Citations (7)
Title |
---|
Chauvett et al, J. Org. Chem. vol. 38, pp. 2994-2999, 1973. * |
Kaiser et al., J. Med. Chem., vol. 14, No. 5, pp. 426-429 (1971). * |
Ochiai et al., J. Chem Soc. Chem. Comm., 1972, pp. 800-801. * |
Ochiai et al., J. Chem Soc., Perkin I, 1974 pp. 258-262. * |
Ochiai et al., Tetrahedron Letters, No. 23, pp. 2345-2348, 1972. * |
Ochiai et al., Tetrahedron, vol. 31, pp. 115-122, 1975. * |
Wright et al, Chemical Abstracts, vol. 75, 76705c (1971). * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4311837A (en) * | 1979-05-01 | 1982-01-19 | Eli Lilly And Company | Certain heterocyclic thiomethyl derivatives of 7-(dihalogenated phenylthioacetamido)cephalosporanic acids useful in the treatment of infections caused by _Streptococcus faecalis |
Also Published As
Publication number | Publication date |
---|---|
IE46175B1 (en) | 1983-03-23 |
DE2754742A1 (de) | 1978-06-15 |
JPS6118554B2 (sl) | 1986-05-13 |
DE2754742C2 (de) | 1986-04-30 |
AU3038677A (en) | 1979-05-17 |
JPS5373597A (en) | 1978-06-30 |
AU511186B2 (en) | 1980-07-31 |
GB1591460A (en) | 1981-06-24 |
IE46175L (en) | 1978-06-08 |
CH626089A5 (sl) | 1981-10-30 |
CA1087169A (en) | 1980-10-07 |
FR2373549B1 (sl) | 1980-12-05 |
NL7712900A (nl) | 1978-06-12 |
FR2373549A1 (fr) | 1978-07-07 |
BE861639A (fr) | 1978-06-08 |
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